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Mattheisen, Manuel

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Mattheisen

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Mattheisen, Manuel

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Author's Publications: search.filters.isAuthorOfPublication.00d774a5-c6a1-4848-916b-e7c1e432044f

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    Gene-Based Analysis of Regionally Enriched Cortical Genes in GWAS Data Sets of Cognitive Traits and Psychiatric Disorders
    (Public Library of Science, 2012) Ersland, Kari M.; Christoforou, Andrea; Stansberg, Christine; Espeseth, Thomas; Mattingsdal, Morten; Hardarson, Gudmundur A.; Hansen, Thomas; Fernandes, Carla P. D.; Giddaluru, Sudheer; Breuer, René; Strohmaier, Jana; Djurovic, Srdjan; Nöthen, Markus M.; Rietschel, Marcella; Lundervold, Astri J.; Werge, Thomas; Cichon, Sven; Andreassen, Ole A.; Reinvang, Ivar; Steen, Vidar M.; Le Hellard, Stephanie; Mattheisen, Manuel
    Background: Despite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain. It has been suggested that genes preferentially, or specifically, expressed in one region or organ reflect functional specialisation. Employing a gene-based approach to the analysis, we used the regionally enriched cortical genes to mine a genome-wide association study (GWAS) of the Norwegian Cognitive NeuroGenetics (NCNG) sample of healthy adults for association to nine psychometric tests measures. In addition, we explored GWAS data sets for the serious psychiatric disorders schizophrenia (SCZ) (n = 3 samples) and bipolar affective disorder (BP) (n = 3 samples), to which cognitive impairment is linked. Principal Findings: At the single gene level, the temporal cortex enriched gene RAR-related orphan receptor B (RORB) showed the strongest overall association, namely to a test of verbal intelligence (Vocabulary, P = 7.7E-04). We also applied gene set enrichment analysis (GSEA) to test the candidate genes, as gene sets, for enrichment of association signal in the NCNG GWAS and in GWASs of BP and of SCZ. We found that genes differentially expressed in the temporal cortex showed a significant enrichment of association signal in a test measure of non-verbal intelligence (Reasoning) in the NCNG sample. Conclusion: Our gene-based approach suggests that RORB could be involved in verbal intelligence differences, while the genes enriched in the temporal cortex might be important to intellectual functions as measured by a test of reasoning in the healthy population. These findings warrant further replication in independent samples on cognitive traits.
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    Replication of Functional Serotonin Receptor Type 3A and B Variants in Bipolar Affective Disorder: A European Multicenter Study
    (Nature Publishing Group, 2012) Hammer, C; Cichon, S; Mühleisen, T W; Haenisch, B; Degenhardt, F; Breuer, R; Witt, S H; Strohmaier, J; Oruc, L; Rivas, F; Babadjanova, G; Grigoroiu-Serbanescu, M; Röth, R; Rappold, G; Rietschel, M; Nöthen, M M; Niesler, B; Mattheisen, Manuel; Hauser, J
    Serotonin type 3 receptors (\(5-HT_3\)) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the \(HTR3A\) and \(HTR3B\) genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P=0.009, 95% confidence intervals=0.802–0.968) for the non-synonymous functional SNP \(HTR3B\) p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR=0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of \(HTR3A\) and \(HTR3B\) mRNA in the human brain. \(HTR3A\) and \(HTR3B\) were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired \(5-HT_3\) receptor function in BPAD.